Under normal physiologic conditions, the immune checkpoints are crucial for maintaining self-tolerance (i.e. prevent autoimmunity) and for modulating the immune response to protect against tissue damage when the immune system is responding to pathogenic infections. At times, tumor cells can co-opt certain immune checkpoint pathways to escape from immunesurveillance mechanisms. Inhibition of immune checkpoints has therefore emerged as a promising approach in cancer immunotherapy. The two immune checkpoint receptors that have been most actively studied in this context are the cytotoxic T-lymphocyte-associated antigen (CTLA-4; also known as CD152) and programmed cell death protein 1 (PD-1; also known as CD279), which regulate the immune response at different levels. CTLA-4 primarily regulates immune responses early in T-cell activation, whereas PD-1 primarily limits the activity of T-cells in the effector phase within tissues and tumors (Pardoll, 2012, Nat. Rev. Cancer, 12:252-64).
PD-1 has two known ligands: programmed death-ligand 1 (PD-L1; also known as human B7 homolog 1, B7-H1, or cluster of differentiation 274, CD274) and programmed death-ligand 2 (PD-L2; also known as B7-DC and CD273). Both ligands belong to the B7 immunoglobulin superfamily and are type I transmembrane glycoproteins composed of IgC- and IgV-type extracellular domains. However, it was recently reported that PD-L1 and PD-L2, as well as PD-1, also exist in soluble forms in addition to being membrane bound. PD-L1 and PD-L2 share approximately 40% amino acid residue identity. Whereas the expression of PD-L2 is mainly limited to antigen presenting cells, PD-L1 is expressed in both hematopoietic and non-hematopoietic cells. High tumor expression of PD-L1 is associated with increased aggressiveness and worse prognosis (Dai et al, 2014, Cellular Immunology, 290:72-79).
The clinical significance of targeting immune checkpoint pathways has been demonstrated with several monoclonal antibodies inhibiting CTLA-4, PD-1 and PD-L1, which work by restoring protective immune responses to tumor cells. The anti-CTLA-4 antibody ipilimumab (Yervoy®, Bristol Myers Squibb) was approved by FDA in 2011 for the treatment patients with metastatic melanoma where a durable response was observed in 10-15% of the patients. However, ipilimumab is associated with immune-related toxicities, potentially due to its role in the priming phase of the immune response thereby also affecting normal tissues. A safer approach may be to target the PD-1/PD-L1 pathway to restore anti-tumor immunity selectively within the tumor microenvironment. Inhibition of the PD-1/PD-L1 pathway has demonstrated durable response in 30-35% of patients with advanced melanoma, which in 2014 resulted in the FDA approval of the anti-PD-1 antibodies pembrolizumab (formerly lambrolizumab; Keytruda®, Merck) and nivolumab (Bristol Myers Squibb and Ono Pharmaceutical) (Shin and Ribas, 2015, Curr. Opin. Immunol., 33:23-35; Philips and Atkins, 2015, International Immunology, 27:39-46). The first PD-L1 targeting antibody investigated in clinical trials was MDX-1105 which was evaluated in a Phase I study in patients with advanced solid tumors including melanoma, non-small cell lung cancer (NSCLC), colorectal cancer, renal cell carcinoma, ovarian cancer, pancreatic cancer, gastric cancer and breast cancer (Momtaz and Postow, 2014, Pharmgenomics Pers Med. 7:357-65). The results demonstrated potential benefits of PD-L1 blockade. Other antibodies against PD-L1 that are currently in Phase III clinical trials include atezolizumab (MDPL3280A, Genentech), durvalumab (MED14736, Medlmmune/Astra Zeneca, Celgene), and avelumab (MSB0010718C, EMD Serono, Pfizer).
To improve the efficacy and increase the number of patients that respond to immunotherapy, it may be beneficial to target the antitumor immune response at multiple levels. This may be achieved through synergistic combinations. For instance, preclinical studies combining CTLA-4 and PD-1 blocking antibodies (ipilimumab and nivolumab) has demonstrated superior antitumor activity, but with a toxicity similar to anti-CTLA-4 monotherapy (Shin and Ribas, 2015, supra). Furthermore, PD-L1 is speculated to be a potential biomarker, due to its abundance in the tumor microenvironment and because tumor expression of PD-L1 has a strong association with response to anti-PD-1/PD-L1 therapy.
The high prevalence of cancer and infectious diseases, together with a high unmet medical need, warrants the development of new modes of treatment. Since tissue penetration rate is negatively associated with the size of the molecule, a relatively large antibody molecule inherently has poor tissue distribution and penetration capacity.
Thus, the use of monoclonal antibodies is not always optimal for therapy and there is continued need for provision of agents with a high affinity for PD-L1. Of great interest is also the provision of uses of such molecules in the treatment, diagnosis and prognosis of PD-L1 related disorders.